Current recommended therapy for the prevention of organ transplantation rejection and related disorders, including graft versus host disease, traditionally involves patient treatment with cyclosporin A and adjunctive therapy with corticosteroids and other immunosuppressive drugs (Jacobs and Elgin, "Cyclosporin A, Current Status, Including the Cape Town Experience" in Immune Modulation Agents and Their Mechanisms, ISBN 0-8247-7178-8, 1984, pp. 191-228; Transplantation and Clinical Immunology, Volume XX Combined Immuno-suppressive Therapy in Transplantation ISBN 0-444-81068-4, 1989).
Presently, cyclosporin A (CSA), an immunosuppressive agent, used in combination with other adjunctive therapies, such as azathioprine and corticosteroids, is the treatment of choice for the prevention of organ transplantation rejection. Other immunosuppressive agents such as azathioprine (AZA), corticosteroids (such as prednisone), OKT3, FK506, mycophenolic acid or the morpholine ethyl ester thereof, 15-deoxyspergualin, rapamycin, mizoribine, misoprostol and anti-interleukin-2 receptor antibodies, have been used or have been suggested to be useful in the treatment and/or prevention of organ transplantation rejection.
Use of any of these known immunosuppressive compounds, either alone or in combination, is associated with a high incidence of side effects such as nephrotoxicity and/or hepatotoxicity. Thus, there presently exists a need for improved therapies to replace or to be used in combination with CSA or other currently known immunosuppressive drugs for the treatment of cancer and for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis.
The 2-carbocyclic and 2-heterocyclic quinolinecarboxylic acids of the present invention are potent inhibitors of dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine nucleotide biosynthesis pathway, and therefore have a unique mechanism of action (inhibition of dihydroorotate dehydrogenase) which is distinct from other available immunosuppressive agents. The compounds of the present invention will be useful as single therapy agents as well as agents to be used in combination with other compounds currently used in these clinical regimens such as CSA. The compounds of the present invention should be useful to permit the administration of reduced doses of other immunosuppressive agents cyclosporin A (CSA or CsA) and analogs thereof, FK506 (or FK-506) and analogs thereof, corticosteroids, azathioprine (AZA), mycophenolic acid or the morpholine ethyl ester thereof, mycophenolate mofetil, rapamycin, 15-deoxyspergualin, mizoribine, leflunomide, OKT3, anti-interleukin-2 receptor antibodies, misoprostol, methotrexate, cyclophosphamide, and anti-lymphocyte/thymocyte serums, used in combination therewith, thereby reducing the adverse effects of these agents.
U.S. Pat. No. 4,680,299 (Hesson) discloses 2-phenyl-4-quinolinecarboxylic acids as tumor-inhibiting agents. Additional utilities for these compounds in the treatment of skin and epithelial diseases and as immunomodulatory or immunosuppressive agents are disclosed in U.S. Pat. No. 4,861,783 (Ackerman et al.) and U.S. Pat. No. 4,968,701, (Ackerman et al.). U.S. Pat. No. 5,204,329 (Ackerman et al.) describes the use of these compounds in combination with a second immunosuppressive agent for the treatment of transplantation rejection and other disease conditions.
Additional examples of 2-phenyl-4-quinolinecarboxylic acids useful in the treatment of arthritis and for inducing immunosuppression are disclosed in U.S. Pat. No. 4,847,381 (Sutherland et al.) and in U.S. Pat. No. 4,968,702 (Poletto et al.).
Buu-Hoi and Lavit [J. Chem. Soc., 2412 (1956)] disclose the compound of the structure shown below. No utility is claimed. ##STR1##
Buu-Hoi and Cagniant [Chem. Bet., 76, 1269 (1943)]describe preparation of the compound shown below. No utility is claimed. ##STR2##
Nguyen et al. [Tap Chi Hoa Hoc, 27 (1), 27 (1989)]detail the preparation of the compound shown below, but claim no utility for the compound. ##STR3##
U.S. Pat. No. 3,799,929 (Holmes) describes the synthesis of the antibacterial compounds shown below, in which R is either H or methyl. ##STR4##
Spada et al.(WO92/20642) disclose compounds of the structure below, in which R is H or phenylsulfonyl, as effective in the treatment of psoriasis, atherosclerosis and vascular reocclusion. ##STR5##
It has now been found that the carbocyclic and heterocyclic quinolinecarboxylic acid compounds described herein are useful for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis, in a mammal. There are no literature references disclosing compounds of the present invention, or derivatives thereof, or their use in treating and/or preventing immunologic disorders.
The 2-carbocyclic and 2-heterocyclic quinolinecarboxylic acid compounds of this invention can be used alone or in combination with one or more additional known immunosuppressive agents, such as cyclosporin A (CSA or CsA) and analogs thereof, FK506 (or FK-506) and analogs thereof, corticosteroids, azathioprine (AZA), mycophenolic acid or the morpholine ethyl ester thereof, mycophenolate mofetil, rapamycin, 15-deoxyspergulin, mizoribine, leflunomide, OKT3, anti-interleukin-2 receptor antibodies, misoprostol, methotrexate, cyclophosphamide, and anti-lymphocyte/thymocyte serums, thereby to reduce the dosage required and associated adverse effects of these immunosuppressive agents.
The isolation of the FK506 is described in European Patent Application publication number 240,773, published Oct. 14, 1987 and the chemical synthesis of FK506 is described by Jones et al.(J. Am. Chem. Soc., 111, 1157 (1989).
The preparation of azathioprine is described in U.S. Pat. No. 3,056,785 issued to Burroughs Wellcome. Azathioprine is available as Imuran.RTM., for which the product information, including dosage and administration, is given in Physicians'Desk Reference 44th Edition, 1990, pp. 777-778.
The preparation of cyclosporin is described in U.S. Pat. No. 4,117,118 issued to Sandoz. Cyclosporin A is available as Sandimmune.RTM., for which the product information, including dosage and information, is given in Physicians'Desk Reference 44th Edition, 1990, pp. 1950-1952.
The preparation of prednisone is described in U.S. Pat. Nos. 2,897,216 and 3,134,718 issued to Schering. Prednisone is available commercially from several manufacturers as are other corticosteroids (see generally, Physicians'Desk Reference, supra).
Murine monoclonal antibody to the human T3 antigen (herein referred to as OKT3) is available as Orthoclone OKT.RTM.3, for which the product information, including dosage and administration and references to methods of preparation, is given in Physicians'Desk Reference, 1990, pp. 1553-1554.
The preparation of mycophenolic acid is described in British Patents 1,157,099; 1,157,100; and 1,158,387 issued to ICI.
15-deoxyspergulin is a derivative of spergualin discovered in culture filtrates of the bacterial strain BGM162-aFZ as reported in Ochiai et al. Prolongation of Rat Heart Allograft Survival by 15-deoxyspergulin, J. Antibiot. (Tokyo), 40, 249 (1987).
Mizoribine is described in U.S. Pat. No. 3,888,843 issued to Toyo Jozo.
Misoprostol, a prostaglandin (PGE1) analog, is described in U.S. Pat. No. 3,965,143 assigned to Searle and U.S. Pat. No. 4,132,738 assigned to Miles.
Rapamycin is described in U.S. Pat. Nos. 4,650,803; 4,316,885; 4,885,171; 3,993,749 and 3,929,992, all assigned to Ayerst.
Antibodies to the IL-2 receptor protein are described in U.S. Pat. Nos. 4,578,335 and 4,845,198 (Immunex) and U.S. Ser. No. 7/341,361 and U.S. Pat. 4,892,827 issued to Pastan et al.